Activated human phagocytes employ the myeloperoxidase-H2O2-Cl system to convert L-tyrosine into the amphipathic aldehyde, p-hydroxyphenylacetaldehyde (pHA). We have explored the possibility that pHA covalently reacts with proteins, which may play a role in modifying targets at sites of inflammation. Purified pHA rapidly reacted with A2-acetyllysine, an analog of protein lysine residues. After reductin with NaCNBH3 the reaction product was identified as Na-acetyl-N3-p-hydroxyphenylethyllysine by 1H NMR spectroscopy and mass spectrometry. p-Hydroxyphenylethyllysine (pHA-lysine) was likewise formed on BSA exposed to l-tyrosine and the myeloperoxidase_H2O2-Cl system. Incubation of BSA and L-tyrosine with a variety of in vitro oxidation systems demonstrated that pHA-lysine is a specific marker for protein modification by myeloperoxidase. pHA-Lysine was formed in BSA exposed to activated neutrophils and L-tyrosine. Because pHA-lysine is a specific marker of protein modificat ion by myeloperoxidase, its identification may pinpoint targets where phagocytes inflict oxidative damage in vivo.